Mutations of the PIK3CA gene in human cancers

Abstract

Phosphatidylinositol 3-kinases (PI3Ks) are known to be important regulators of signaling pathways. To determine whether PI3Ks are genetically altered in cancers, we analyzed the sequences of the PI3K gene family and discovered that one family member, PIK3CA, is frequently mutated in cancers of the colon and other organs. The majority of mutations clustered near two positions within the PI3K helical or kinase domains. PIK3CA represents one of the most highly mutated oncogenes yet identified in human cancers and is useful as a diagnostic and therapeutic target.

We claim: 
     
       1. A method for treating a cancer in a subject, comprising:
 detecting in a body sample obtained from the subject a presence of a PIK3CA mutation by a sequencer and identifying the subject as having the PIK3CA mutation, wherein the PIK3CA mutation is at least one mutation selected from the group consisting of: C112T, G113A, G263A, C311G, G317T, G323C, del332-334, G353A, G365A, C370A, T1035A, G1048C, T1132C, T1258C, G1357C, C1616G, G1624A, A1625G, A1625T, G1633A, A1634G, G1635T, C1636A, A1637C, C1981A, A2102C, G2702T, T2725C, T3022C, A3073G, C3074A, G3129T, C3139T, A3140T, and G3145A, the positions of said PIK3CA mutations being in accordance with a nucleotide sequence of SEQ ID NO. 1; and 
 administering a p110α inhibitor to the subject identified as having the PIK3CA mutation, thereby treating the cancer. 
 
     
     
       2. The method according to  claim 1 , wherein the detecting comprises:
 (i) amplifying a PIK3CA polynucleotide in the body sample to synthesize an amplicon, wherein the PIK3CA polynucleotide comprises the at least one mutation, and the amplicon comprising the at least one mutation; and 
 (ii) sequencing the amplicon produced in the amplifying by the sequencer to detect the presence of the at least one mutation in the amplicon, wherein the presence of the at least one mutation in the amplicon indicates the presence of the PIK3CA mutation in the sample and identifies the subject as having the PIK3CA mutation. 
 
     
     
       3. The method according to  claim 1 , wherein the body sample is obtained from a tissue. 
     
     
       4. The method according to  claim 1 , wherein the body sample is a colorectal tissue, a brain tissue, a gastric tissue, a breast tissue, a lung tissue, blood, sputum, saliva, urine, stool or nipple aspirate. 
     
     
       5. The method according to  claim 1 , wherein the body sample comprises blood, serum, or plasma. 
     
     
       6. The method according to  claim 1 , wherein the subject is a cancer patient. 
     
     
       7. The method according to  claim 1 , wherein the subject has a cancer selected from the group consisting of: colorectal cancer, glioblastoma, gastric cancer, breast cancer, lung cancer, pancreatic cancer, medulloblastoma, and adenoma. 
     
     
       8. The method according to  claim 2 , wherein the amplifying is performed using a thermal cycler. 
     
     
       9. The method according to  claim 2 , wherein the PIK3CA polynucleotide is amplified by PCR in the amplifying. 
     
     
       10. The method according to  claim 2 , wherein the sequencing is performed using a sequencing primer. 
     
     
       11. The method according to  claim 2 , wherein sequence information of the amplicon obtained in the sequencing is compared to at least one sequence selected from the group consisting of a sequence of a wild type PIK3CA gene and a sequence of a mutated PIK3CA gene to detect the presence of said at least one mutation. 
     
     
       12. A method for treating a cancer in a subject, comprising:
 sequencing a PIK3CA gene in a body sample obtained from the subject to detect a presence of a PIK3CA mutation by a sequencer and identifying the subject as having the PIK3CA mutation, wherein the PIK3CA mutation is at least one mutation selected from the group consisting of: C112T, G113A, G263A, C311G, G317T, G323C, del332-334, G353A, G365A, C370A, T1035A, G1048C, T1132C, T1258C, G1357C, C1616G, G1624A, A1625G, A1625T, G1633A, A1634G, G1635T, C1636A, A1637C, C1981A, A2102C, G2702T, T2725C, T3022C, A3073G, C3074A, G3129T, C3139T, A3140T, and G3145A, the positions of said PIK3CA mutations being in accordance with a nucleotide sequence of SEQ ID NO. 1; and 
 administering a p110α inhibitor to the subject identified as having the PIK3CA mutation, thereby treating the cancer. 
 
     
     
       13. The method according to  claim 12 , further comprising:
 before sequencing, amplifying PIK3CA polynucleotide in the body sample to synthesize an amplicon, wherein the PIK3CA polynucleotide comprises the at least one mutation, and the amplicon comprising the at least one mutation; and 
 wherein the sequencing comprises sequencing the amplicon produced in the amplifying to detect the presence of the at least one mutation in the amplicon, wherein the presence of the at least one mutation in the amplicon indicates the presence of the PIK3CA mutation in the sample and identifies the subject as having the PIK3CA mutation. 
 
     
     
       14. The method according to  claim 12 , wherein the body sample is a colorectal tissue, a brain tissue, a gastric tissue, a breast tissue, a lung tissue, blood, sputum, saliva, urine, stool or nipple aspirate. 
     
     
       15. The method according to  claim 12 , wherein the subject has a cancer selected from the group consisting of: colorectal cancer, glioblastoma, gastric cancer, breast cancer, lung cancer, pancreatic cancer, medulloblastoma, and adenoma. 
     
     
       16. The method according to  claim 12 , wherein a sequence information of the amplicon obtained in the sequencing is compared to at least one sequence selected from the group consisting of a sequence of a wild type PIK3CA gene and a sequence of a mutated PIK3CA gene to detect the presence of said at least one mutation. 
     
     
       17. A method for administering a drug to a cancer patient, comprising:
 detecting in a body sample obtained from the cancer patient a presence of a PIK3CA mutation by a sequencer and identifying the subject as having the PIK3CA mutation, wherein the PIK3CA mutation is at least one mutation selected from the group consisting of: C112T, G113A, G263A, C311G, G317T, G323C, del332-334, G353A, G365A, C370A, T1035A, G1048C, T1132C, T1258C, G1357C, C1616G, G1624A, A1625G, A1625T, G1633A, A1634G, G1635T, C1636A, A1637C, C1981A, A2102C, G2702T, T2725C, T3022C, A3073G, C3074A, G3129T, C3139T, A3140T, and G3145A, the positions of said PIK3CA mutations being in accordance with a nucleotide sequence of SEQ ID NO. 1; and 
 administering a p110α inhibitor to the cancer patient identified as having the PIK3CA mutation. 
 
     
     
       18. The method according to  claim 17 , wherein the body sample is a colorectal tissue, a brain tissue, a gastric tissue, a breast tissue, a lung tissue, blood, sputum, saliva, urine, stool or nipple aspirate. 
     
     
       19. The method according to  claim 17 , wherein the cancer patient has a cancer selected from the group consisting of colorectal cancer, glioblastoma, gastric cancer, breast cancer, lung cancer, pancreatic cancer, medulloblastoma, and adenoma.